Translating from mouse to man to better understand immune-mediated inflammatory diseases
Authors: Dominik Aschenbrenner, Richard M. Siegel
Journal: Cell Reports Medicine (2023)

Lilja et al.1Lilja S. Li X. Smelik M. Lee E.J. Loscalzo J. Marthanda P.B. Hu L. Magnusson M. Sysoev O. Zhang H. et al.Multi-organ single cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases.Cell Rep. Med. 2023; 4https://doi.org/10.1016/j.xcrm.2023.100956Abstract Full Text Full Text PDF Scopus (2) Google Scholar explore single-cell transcriptomes across multiple organs of mice with collagen-induced arthritis. They apply network analysis to prioritize functional pathways that support or suppress inflammation and integrate findings with tissue transcriptomics in human immune-mediated inflammatory diseases. Lilja et al.1Lilja S. Li X. Smelik M. Lee E.J. Loscalzo J. Marthanda P.B. Hu L. Magnusson M. Sysoev O. Zhang H. et al.Multi-organ single cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases.Cell Rep. Med. 2023; 4https://doi.org/10.1016/j.xcrm.2023.100956Abstract Full Text Full Text PDF Scopus (2) Google Scholar explore single-cell transcriptomes across multiple organs of mice with collagen-induced arthritis. They apply network analysis to prioritize functional pathways that support or suppress inflammation and integrate findings with tissue transcriptomics in human immune-mediated inflammatory diseases. Despite the increasing flood of data, translating insights from molecular profiling studies of human immune-mediated inflammatory diseases (IMIDs) and their animal models into novel strategies for patient stratification and precision medicine remains a major challenge. One of the enigmas of IMIDs is that primary and secondary organ manifestations can be quite specific compared with autoimmunity seen against ubiquitous antigens. In addition, the pattern of affected organs varies between individuals with the same IMID.2Robinson D. Hackett M. Wong J. Kimball A.B. Cohen R. Bala M. IMID Study Group Co-occurrence and comorbidities in patients with immune-mediated inflammatory disorders: an exploration using US healthcare claims data, 2001–2002.Curr. Med. Res. Opin. 2006; 22: 989-1000https://doi.org/10.1185/030079906x104641Crossref PubMed Scopus (0) Google Scholar,3El-Gabalawy H. Guenther L.C. Bernstein C.N. Epidemiology of immune-mediated inflammatory diseases: Incidence, prevalence, natural history, and comorbidities.J. Rheumatol. Suppl. 2010; 85: 2-10https://doi.org/10.3899/jrheum.091461Crossref PubMed Scopus (150) Google Scholar Furthermore, disease course and response to targeted therapies also vary widely across distinct IMIDs and between patients with the same IMID. For example, anti-tumor necrosis factor (TNF) biologics are effective in subgroups of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), inflammatory bowel disease (IBD) comprising Crohn's disease (CD), and ulcerative colitis (UC). Anti-interleukin-17A (IL-17A)-targeting biologics are effective in subgroups of patients with PsA, AS, and psoriasis (PsO) but not in patients with IBD.4Maxwell J.R. Zhang Y. Brown W.A. Smith C.L. Byrne F.R. Fiorino M. Stevens E. Bigler J. Davis J.A. Rottman J.B. et al.Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation.Immunity. 2015; 43: 739-750https://doi.org/10.1016/j.immuni.2015.08.019Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar This has prompted a re-classification of diseases into cytokine-driven classes, but this framework still does not explain the organ specificity of IMIDs.5Schett G. McInnes I.B. Neurath M.F. Reframing immune-mediated inflammatory diseases through signature cytokine hubs.N. Engl. J. Med. 2021; 385: 628-639https://doi.org/10.1056/nejmra1909094Crossref PubMed Scopus (0) Google Scholar Unraveling the mechanistic basis of tissue-level regulation of inflammation at the organ and organism levels across IMIDs may provide novel insights into shared and distinct features of specific diseases and facilitate the development of innovative therapies, treatment prioritization, and patient stratification strategies for precision medicine. Lilja et al.1Lilja S. Li X. Smelik M. Lee E.J. Loscalzo J. Marthanda P.B. Hu L. Magnusson M. Sysoev O. Zhang H. et al.Multi-organ single cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases.Cell Rep. Med. 2023; 4https://doi.org/10.1016/j.xcrm.2023.100956Abstract Full Text Full Text PDF Scopus (2) Google Scholar present an analysis method based on gene expression changes through single-cell RNA sequencing (scRNA-seq) in multiple organs of mice induced to develop collagen-induced arthritis (CIA) to prioritize intercellular pathways dysregulated in the joints and other organs. Based on these tissue-specific single-cell transcriptomes, the authors identify transcriptional changes at inflamed sites (e.g., paws) and sites with no histologic evidence of tissue inflammation (e.g., muscle) and relate these to upregulated functional pathways in cell types of paw origin, including fibroblasts, T cells, endothelial cells, macrophages, and epithelial cells, and downregulated functional pathways in cell types of muscle origin, including natural killer (NK) cells, endothelial cells, dendritic cells, B cells, and monocytes. Based on the similarity of regulated pathways in inflamed and non-inflamed tissue, Lilja et al. describe upstream regulators to construct a multi-organ model and establish a hierarchy of bidirectionally regulated pathways and higher-order functional programs in inflammation or homeostasis. Focusing on the top-ranking upstream regulators, the authors identify distinct patterns of Il1b and Tnf response in inflammation and homeostasis and relate this to the inverse expression of anti-inflammatory Tgfb, for which related pathway activity was elevated in muscle tissue where no signs of inflammation could be detected in diseased animals. Translating findings from mouse models of IMIDs to actionable targets in human disease pathogenesis is limited by the specific nature of the immunogen and genetic homogeneity of these models, making them more akin to studying one patient subgroup or a rare genetic disease. Beyond that, transcriptional programs of orthologous immune-regulatory and cytokine genes can vary considerably between mouse and human.6Shay T. Jojic V. Zuk O. Rothamel K. Puyraimond-Zemmour D. Feng T. Wakamatsu E. Benoist C. Koller D. Regev A. ImmGen Consortium Conservation and divergence in the transcriptional programs of the human and mouse immune systems.Proc. Natl. Acad. Sci. USA. 2013; 110: 2946-2951https://doi.org/10.1073/pnas.1222738110Crossref PubMed Scopus (235) Google Scholar It is thus critical to study human disease relevance of findings in animal models. To this end, Lilja et al. categorize gene expression datasets from bulk RNA-seq of healthy, unaffected, and affected tissues from ten human IMIDs into pathway programs, revealing a gradual shift from anti- to pro-inflammatory programs. The authors further extend these analyses to gene expression programs in biopsies from patients with IBD stratified by responsiveness to anti-TNF therapy and identify response- and non-response-related upstream regulators, highlighting NR4A2- and TLR6-related pathway activity in anti-TNF non-responders. Finally, Lilja et al. investigate the potential of their analysis strategy for patient stratification in systemic lupus erythematosus (SLE), identifying upstream regulators of disease activity and organ damage. These efforts highlighted associations of oncostatin M (OSM) with both disease activity and organ damage in patients with lupus nephritis (LN) and associations of CD40 with disease activity and CD40-L with organ damage in patients without LN. Despite these promising results, several limitations remain, including (1) how these results compare with other animal models of joint-specific inflammation such as the serum-transfer arthritis model or spontaneous disease models, (2) how much the perturbations of gene regulatory networks are caused by the adjuvant used in the CIA model vs. the induced disease state, and (3) how animal model-derived data can optimally be integrated with human tissue data. The current study also does not cover longitudinal aspects of IMIDs such as cycles of inflammation and resolution, which are common in human disease progression and can be seen in some animal models. Despite these limitations, the results of Lilja et al. represent a promising network modeling-based approach to facilitate a holistic analysis of gene expression in multiple organs, contrasting mechanisms that balance inflammation and homeostasis in affected and unaffected tissues, pinpointing key upstream regulators, and highlighting contrast between systemic immune dysregulation and organ-specific tissue inflammation that characterize IMIDs. R.M.S. and D.A. are employees and shareholders of Novartis. This article reflects the authors' personal opinions and not that of their employer. Multi-organ single-cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseasesLilja et al.Cell Reports MedicineFebruary 28, 2023In BriefLilja et al. report that treating immune diseases is complicated by involvement of thousands of genes. Combined analyses of mouse arthritis and human immune diseases show organome-, cellulome-, and genome-wide changes, which are switched on or off by pro- or anti-inflammatory upstream regulators (URs). Targeting URs may contribute to personalized medicine. Full-Text PDF Open Access